Benzodiazepines are often used in the effective management of ethanol withdrawal seizures. These drugs are believed to act through their effects on GABA receptors. Recent studies have led to the suggestion that GABA-receptive neurons of the substantia nigra may be a primary site of action of these drugs. In addition, since both acute and chronic ethanol produce prominent changes in GABAergic neurotransmission, alterations in the function of GABAergic or GABA-receptive neurons in either substantia nigra or some other site may be directly involved in the changes in seizure susceptibility which occur during ethanol withdrawal. The proposed project will investigate the role of specific neuronal sites in the modulation of ethanol withdrawal seizures, motor convulsions, and other withdrawal signs. The involvement of the amygdala, hippocampus, inferior colliculus, and substantia nigra in the ethanol withdrawal syndrome will be studied by examining the effects of direct injections into those sites on specific aspects of the withdrawal syndrome in an animal model of chronic ethanol exposure. This will include studies of the effects of cannula-instilled muscimol (a GABA receptor blocker), strychnine (a glycine antagonist), and CL 218,782 (a specific GABA receptor agonist), flurazepam (a benzodiazepine which potentiates GABAergic neurotransmission), bicucullin (a GABA Type 1 receptor agonist) on the withdrawal syndrome elicited upon removal from a regimen of chronic ethanol exposure. The dependent variables to be examined will include measures of pre-seizure spike activity and sustained epileptiform seizures at cortical and subcortical sites and several behavioral measures of the ethanol withdrawal syndrome, including motor convulsions. Correlations between the electrophysiological activity of various sites will be determined, as will correlations between neural activity and behavioral measures of withdrawal. Additional studies will be conducted to determine the effects of ethanol withdrawal on single-unit activity and on the responsiveness of GABA-receptive neurons to locally-applied GABA agonists and antagonists. These studies should provide a greater understanding of the mechanisms which operate to modulate the symptoms which accompany ethanol withdrawal. In particular, the investigation of site-specific drug effects on the expression of physical dependence on ethanol may lead to the development of more effective drugs for the treatment of ethanol withdrawal by allowing the targeting of drugs to specific active sites.